Chronic cutaneous wounds pose significant health problems for Veterans with diverse medical conditions, including wartime-sustained trauma, spinal cord injury, diabetes and vascular insufficiency. Wound healing is a highly regulated process involving cell migration, proliferation and secretion of extracellular matrix proteins. Dysregulation of these cellular and molecular signaling cascades may result in either excessive healing (keloid scar formation) or inadequate healing in patients with diabetes, vascular insufficiency, or burns. Stem cell transplantation carries great promise in the field of regenerative medicine and has been shown to contribute to regenerative wound healing in some pre-clinical models. However, the current unavailability of molecularly-defined, pure stem cell populations with established functional relevance of employed isolation markers, and the limited capacity of available stem cell populations to regenerate normal skin appendages, represent significant barriers to broader therapeutic benefit and eventual successful translation of stem cell-based treatment strategies to the clinic. This study aims to address these obstacles by establishing a novel stem cell-based approach to regenerative wound healing that employs a newly discovered dermal stem cell population with multipotent in vitro and in vivo differentiation plasticity, defined by expression of the ATP-bindig cassette transporter, ABCB5. Based on our findings of multipotent differentiation plasticity of thi novel stem cell population, fortified by our demonstration of functional roles of ABCB5 in stem cell self-renewal, normal skin development and wound healing in newly created ABCB5 knockout mice, we hypothesize that human ABCB5+ dermal stem cell grafting will significantly improve regenerative wound healing in translationally relevant syngeneic humanized transplantation models. As a result, this initiative is anticipated to pave the way towards eventual successful application of novel personalized stem cell-based treatment modalities for Veterans afflicted by cutaneous wounds, a major source of morbidity and mortality. PUBLIC HEALTH RELEVANCE: Chronic cutaneous wounds pose significant health problems for Veterans with diverse medical conditions such as wartime-sustained trauma, spinal cord injury, diabetes and vascular insufficiency. During recent conflicts in Iraq and Afganistan, many troops experienced severe traumatic injuries, e.g. spinal cord injury and massive burns. Many of these veterans are at risk of developing chronic wounds as a consequence of immobility and pressure ulcers. The current study aims to establish novel personalized stem cell-based therapeutic approaches to regenerative wound healing using stem cells isolated from human skin. Specifically, we will identify a new source of purified multipotent stem cells for transplantation, which will have the potential to substantially increase the success of wound healing in Veterans.